Pharmaceutical agents or drugs exhibit desirable therapeutic properties because they contain distinct molecular arrangements called pharmacophores. Oftentimes, however, the pharmacophores or the presence of other chemical components within such compounds, provide a less than ideal overall profile relative to the final deployment of a given drug for a particular clinical indication. In some cases this situation can be improved by altering chemical features associated with a drug""s distribution, metabolism or elimination (DME). This process, when successful, results in what is now referred to in the pharmaceutical community as a xe2x80x9csoft drugxe2x80x9d version of the original or parent drug compound: Soft Drugs. XX. Design, Synthesis and Evaluation of Ultra-Short Acting beta-Blockers, H.-S. Yang, W.-M, Wu and N. Bodor, Pharm. Res., 12, 329 (1995); and Synthesis and Enzymatic Hydrolysis of Esters, Constituting Simple Models of Soft Drugs, M. Graffner-Nordberg, K. Sjodin, A. Tunek and A. Hallberg, Chem. Pharm. Bull., 46, 591 (1998).
However, unless there is compelling preclinical data which suggests that the clinical application of a lead compound is going to become problematic, DME-related features are typically not rigorously evaluated in a chemical manner during the early process of new drug discovery and development. This situation has arisen, in part, because substantial clinical experience is often required to accurately define the sometimes subtle parameters of an undesirable DME feature relative to the beneficial aspects of a new drug while the latter is within the close purview of its actual clinical use in a specific pathophysiological setting. The problem of not knowing exactly what DME and toxicity-related properties may need to be addressed is additionally confounded by not having ready chemical blueprints for how to generally proceed even when a particular DME or toxicity issue becomes suspected.
The invention disclosed herein provides a ready method for altering DME and toxicity-related properties by deploying a specific chemical blueprint. The approach is useful to initially assess the DME parameters for an entire family of potential new drug candidate possibilities during the family""s very early stages of structural refinement and preclinical study. When applied in this fashion, the inventive method expedites and improves the efficiency of the overall process of drug discovery and development.
Technologies which can enhance the efficiency of the drug discovery and development process have recently become of very high interest to the global pharmaceutical enterprise: Lead Generation and Optimization, Annual Meeting Strategic Research Institute, San Diego, Jun. 23, 1997; Emerging Technologies for Drug Discovery, International Biotechnology Event National Management Health Care Congress, Boston, May 19, 1997; and Pharmaceutical Education, Interim Meeting, American Association Colleges Pharmacy, Washington, D.C., Mar. 2, 1997.
Of equal significance but in more succinct and individually directed applications, the present invention is also useful for modifying the clinically established pharmaceutical agents where the specific therapeutic/side-effect details and benefits that might be associated with such DME alterations to a parent drug molecule are already recognized for a given indication. The current move to individualize drug treatment protocols within the evolving field of pharmacogenetics further underscores the very high interest and importance for having conveniently deployable technologies which can be generally applied toward fine-tuning and tailoring the overall pharmacological profile of a given drug for a given indication within a given individual: Recommendations of the NIGMS Working Group-Understanding Individual Variations in Drug Responses: From Phenotype to Genotype, R. M. Long and R. M. Weinshilboum, NIH Report  less than http://www.hih.gov/nigms/news/reports/pharmacogenetics.html greater than , 5 pages (Jun. 9-10, 1998).
In one aspect, the present invention relates to a method of deploying one or more aralkyl ester moieties or xe2x80x9cmetabophoresxe2x80x9d within a parent drug compound. The aralkyl ester moieties are either co-constructed within the constitutive molecular framework of a parent drug compound or are added onto a parent drug compound as a distinct appendage. These constructions are done in such a manner so as to preserve the parent drug""s therapeutic properties while programming a specific course for the drug""s metabolism. The specific course for the drug""s metabolism leads to inactive or much less active, non-toxic metabolites when the modified drug is then administered to humans by either the oral, inhalation, injection, implantable or topical routes.
Furthermore, the specific molecular details of the aralkyl ester moieties and their various placements within the parent drug""s structure are able to be fine-tuned to precisely control the rate of metabolism. The rate of metabolism, in turn, can be used to control the distribution, the duration of action, the elimination, and/or the toxicity of the resulting soft drug.
The metabophores are useful for all drug types whenever the programmed ester cleavage causes fragmentation of the drug""s inherent pharmacophore or leads to the production of an acidic group that can not somewhere by tolerated by the pharmacophore within the still intact parent drug.
The metabophores are also useful for producing families of closely related compounds for better optimizing the overall pharmacological profiles of new drug candidates during the process of drug design and development.
The metabophores are also useful for enhancement of the overall therapeutic profiles for a wide variety of drugs already being used.
In one aspect, the metabophores are used to program a specific course of innocuous metabolism/elimination in order to circumvent unwanted accumulation and/or toxic pathways otherwise exhibited by the parent drug.
In another aspect, the metabophores are used to program the rate for a specified metabolism in order to adjust the parent drug""s duration of action to a desired shorter time interval. Alternatively, when the aralkyl ester moieties are used in conjunction with an implant or drug depot delivery system, the rate of programmed metabolism can be matched to that for the soft drug""s delivery so as to precisely provide prolonged steady-state levels of the soft drug at pre-calibrated concentrations.
In another aspect, the metabophores are used, to program an ultra-short duration into a parent drug to allow the resulting soft drug""s actions to be under precise moment-to-moment control via its intravenous administration infusion rate, an overall drug property which has already been demonstrated to be particularly useful in critical care and surgical settings. Given the paucity of drugs and drug-related technologies that have been previously targeted for very young humans, the present invention is especially useful in the development of aralkyl ester soft drugs which are conveniently and safely deployed for the specific treatment of premature, full-term newborn or for the perinatal and neonatal populations in general.
In yet another aspect, the metabophores are useful to provide an ultra-short duration drug which allows for localizing the effects of the soft drug when the drug""s initial delivery or activation within a desired compartment can also be achieved in a selective manner (e.g. localized injection, implant, surgical sutures, or localized photodynamic activation).
In still yet another aspect, the metabophores are useful to provide a soft drug pharmacological agent that can be deployed by the intravenous route to wean a patient off of a parent drug whose pharmacological action is more safely removed in a controlled, step-wise manner by progressively decreasing the rate of the intravenous drip of the soft drug version (e.g. avoidance of rebound pharmacological events due to abrupt withdrawal of the parent compound).
In one aspect, the present invention relates to a method and to compositions for treating persistent pulmonary hypertension in human newborns that deploys an intravenous infusion of a modified drug formed by adding one or more of a predetermined chemical arrangement to an efficacious parent drug compound so as to retain efficacy while re-directing a preferred route and rate of the parent drug compound""s metabolism to an inactive or very weakly active and non-oxic metabolite. The chemical arrangement comprises 
where xcfx86 is a phenyl, substituted aryl or heteroaryl system that is already present in the parent drug compound or is specifically added to the parent drug compound via a metabolically stable connection;
R is an alkyl or alkene containing chain either branched or unbranched from 0 to 10 carbons that is already present in the parent drug compound or is added to the parent drug compound via a metabolically stable connection to xcfx86;
X is a carboxyl, sulfoxyl or phosphatyl function that is specifically added to the parent drug compound via a metabolically stable connection to R; and,
Rxe2x80x2 is an added alkyl, alkenyl or aralkyl group either branched or unbranched containing from 1 to 10 carbons, or is a structural element already present as an inherent portion of the parent drug compound.